It has been known for a long time that calcium ion (Ca2+) is important for an intracellular second messenger in the activation of various cells. Intracellular Ca2+ also acts as an important regulatory factor in inflammatory cells. It has been suggested, however, that voltage-operated Ca2+ channel (to be referred to as “VOCC” hereinafter) inhibitors such as nifedipine does not show inhibitory activity against the activation of inflammatory cells and that a Ca2+ influx mechanism other than VOCC exist in inflammatory cells.
Hoth et al. have reported that a Ca2+-selective and Ca2+ store depletion-activated Ca2+ channel, namely Ca2+ release-activated Ca2+ channel (to be referred to as “CRACC” hereinafter; also called store-dependent Ca2+ channel), is present in mast cells and lymphocytes, and these cells are insensitive to membrane potential (Pflugers Arch., 430, pp. 315-322 (1995)). It is known that CRACC is present in several inflammatory cells such as mast cells, lymphocytes, astrocytes (J. Biol. Chem., 270, pp. 29-32 (1995)) and the like, and that it is deeply concerned in, for example, cytokine production and lipid mediator release (J. Immunol., 155, pp. 285-296 (1995) and Br. J. Pharmacol., 114, pp. 598-601 (1995)).
Recently, it has been revealed that tenidap, an agent for treating rheumatoid arthritis, has a potency of CRACC inhibitor (Cell Calcium, 14, pp. 1-16 (1993)). Therefore, a CRACC inhibitor has a possibility of therapeutic potency on chronic inflammatory diseases including rheumatoid arthritis.
It is known that CRACC is also present in endothelial cells (Am. J. Physiol., 269, C 733-738 (1995) ) and epithelial cells (J. Biol. Chem., 270, pp. 169-175 (1995)). Since it has been reported that sustained calcium influx takes a role in the radical affection of endothelial cells (Am. J. Physiol., 261, C 889-896 (1991)), it is suggested that a CRACC inhibitor should have protective efficacy on endothelial cell-concerned tissue damage.
In addition, it has been reported that blockades of calcium influx inhibit cell proliferation and interleukin 2 (IL-2) production (Br. J. Pharmacol., 113, pp. 861-868 (1994)). Therefore, a CRACC inhibitor is useful as an agent for the prevention and treatment of proliferative or progressive diseases (e.g., malignant tumor and the like) and autoimmune diseases, and also as a suppresser for tissue rejection in transplantation.
On the other hand, it is known that in excitable cells such as smooth muscle cells and nerve cells, intracellular calcium is mainly regulated with VOCC not with CRACC. Therefore, it is expected that a calcium channel blocker having CRACC selectivity against VOCC should be an useful agent for the prevention or treatment of various inflammatory diseases, allergic diseases, autoimmune diseases, tissue damages, proliferative diseases and the like without undesirable actions on cardiovascular and central nervous system.
Recently, some compounds showing CRACC inhibitory activity have been reported, such as a cycloalkyl-piperazinylethanol derivative disclosed in a published German patent application 4404249 and a 2-(3,4-dihydro-1-isoquinolyl)acetamide derivative disclosed in WO 94/00435. It has also reported that 5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide inhibits CRACC (J. Pharm. Exp. Ther., 257, pp. 967-971 (1991)). However, there are no reports on a compound whose CRACC selectivity over VOCC has been confirmed.
On the other hand, a published German patent application 2525024 discloses a
5-(heterocycloylaminophenyl)-1-phenylpyrazole derivative which shows an anti-inflammatory activity. However, this patent does not disclose or suggest about its inhibitory activities against CRACC and IL-2 production.
WO 95/18097 discloses an anthranilic acid derivative represented by the following formula, which inhibits a cyclic GMP phosphodiesterase. In the formula, R1 to R4 represent H, a halogen atom, . . . , pyrazolyl which may be substituted, . . . ; n is 0 to 6, W represents N or CH, Y represents O or S, . . . (see said published patent application for details).

An unexamined published Japanese patent application 9-59236 discloses an R1, R2-di-substituted benzamide derivative represented by the following formula, which is useful for the prevention and treatment of rheumatic, allergic and other inflammatory diseases. In the formula, R1 represents a substituted or unsubstituted aromatic heterocyclic ring, . . . , R2 represents a halogen, a nitro, —NR5R6, . . . , A represents —C(═Z)NR3R4 or —NR4C(═Z)R3, R3 represents a substituted or unsubstituted aromatic hydrocarbon ring, a substituted or unsubstituted aromatic heterocyclic ring . . . (see said published patent application for details). However, there is no illustrative disclosure about pyrazolyl as the aromatic heterocyclic ring group. In addition, there is no disclosure about inhibitory activities against CRACC and/or IL-2 production.
